In recent years fundamental advances have been made in the development of chemical agents and regimens of therapy to combat neoplastic diseases. Despite these continuing advances, cancers continue to exact intolerable levels of human pain and suffering. The need for new and better methods of treating neoplasms and leukemias continues to fuel efforts to find new classes of antitumor compounds, especially in the area of inoperable or metastatic solid tumors, such as the various forms of lung cancer. Of the one million new cases of cancer diagnosed in the United States each year, more than 90% represent non-hematopoetic tumors, where improvements in five-year survival rates have been modest, at best. B. E. Henderson, et al., Science, 254:1131-1137 (1991).
The recent avalanche of information regarding the basic biological processes involved in neoplasms has led to a deeper understanding of the heterogeneity of tumors. Ongoing work has led to the realization that individual tumors may contain many subpopulations of neoplastic cells that differ in crucial characteristics, such as karyotype, morphology, immunogenicity, growth rate, capacity to metastasize, and response to antineoplastic agents.
It is because of this extreme heterogeneity among populations of neoplastic cells that new chemotherapeutic agents should have a wide spectrum of activity and a large therapeutic index. In addition, such agents must be chemically stable and compatible with other agents. It is also important that any chemotherapeutic regimen be as convenient and painless as possible to the patient.
This invention reports a series of novel sulfonylureas that are useful in the treatment of solid tumors. These compounds are orally active--which, of course, results in less trauma to the patient--and are relatively non-toxic. These compounds also have an excellent therapeutic index. The compounds and their formulations are novel.
Many sulfonylureas are known in the art. Certain of these compounds are known to have hypoglycemic activities, and have been used medicinally as such agents. In addition, some sulfonylureas have been taught to have herbicidal and antimycotic activities. General reviews of compounds of this structural type are taught by Kurzer, Chemical Reviews, 50:1 (1952) and C. R. Kahn and Y. Shechter, Goodman and Gilman's. The Pharmacological Basis of Therapeutics, (Gilman, et al., 8th ed. 1990) 1484-1487.
Some diarylsulfonylureas have been reported as being active antitumor agents. e.g., U.S. Pat. No. 5,169,860, of F. Mohamadi and M. Spees, issued Dec. 8, 1992; U.S. Pat. No. 4,845,128 of Harper, et al., issued Jul. 4, 1989; U.S. Pat. No. 5,110,830 of Harper, et al., issued May 5, 1992; U.S. Pat. No. 5,116,874 of G. A. Poore, issued May 26, 1992; U.S. Pat. No. 5,216,026, of J. Howbert, issued Jun. 1, 1993; U.S. Pat. No. 5,216,027, of J. E. Ray, et al., issued Jun. 1, 1993; U.S. Pat. No. 5,260,338, of R. W. Harper, et al., issued Nov. 9, 1993; U.S. Pat. No. 5,594,028, of R. W. Harper, et al., issued Jan. 14, 1997; U.S. Pat. No. 5,302,724, of J. J. Howbert, et al., issued Apr. 12, 1994; U.S. Pat. No. 5,270,329, of W. L. Scott, et al., issued Dec. 14, 1993; U.S. Pat. No. 5,234,955, of J. E. Ray, et al., issued Aug. 10, 1993; U.S. Pat. No. 5,354,778, of J. E. Ray, et al., issued Oct. 11, 1994; U.S. Pat. No. 5,258,406, of J. E. Toth, et al., issued Nov. 2, 1993; U.S. Pat. No. 5,262,440, of W. J. Ehlhardt, et al., issued Nov. 16, 1993; U.S. Pat. No. 5,254,582, of G. B. Boder, et al., issued Oct. 19, 1993; U.S. Pat. No. 5,565,494, of G. B. Grindey, et al., issued Oct. 15, 1996; U.S. Pat. No. 5,387,681, of W. D. Miller, et al., issued Feb. 7, 1995; and U.S. Pat. No. 5,529,999, of J. E. Ray, et al., issued Jun. 25, 1996; the entirety of all of which are herein incorporated by reference.